In models of stroke, neurodegenerative disease, and developmental cell death, the delivery of specific neurotrophins can protect neurons from apoptosis. Thus an understanding of the molecular mechanisms that neurotrophins use to promote cell survival and to protect neurons from injury is likely to contribute to the development of novel therapies for neuronal disorders and diseases associated with cell death. Recent studies have firmly established that phosphatidylinositol (PI) 3-kinase and the Akt protein kinase comprise an important cell survival pathway activated by nerve growth factor (NGF) and other neurotrophins. However, it is now becoming clear that neurotrophins utilize additional survival pathways. The overall aim of this application is to test the hypothesis that NGF transduces survival signals through a pathway involving the transcriptional regulator nuclear factor kappa-B (NF-KB). A major theme that will be explored is that NF-kB contributes to NGF-promoted survival by up-regulating anti-apoptotic mechanisms in neurons. Specific aim 1 will investigate the relationship between the PI 3-kinase/Akt and NF-KB survival pathways in neurons. Experiments will test whether inhibiting the PT 3-kinase/Akt pathway effects NGF-induced NF-KB activation in neurons. Additional experiments will examine whether activation of either pathway can protect neurons from cell death caused by inhibiting the other. Experiments in specific aim 2 will determine the cell death events induced after NGF withdrawal that can be blocked by activating NF-kB, focusing on reactive oxygen species, Bax, and cytochrome c. The goal of specific aim 3 is to identify pro-survival transcriptional targets of NF-kB in neurons and to test whether these proteins function as part of a NGF-dependent survival pathway. Experiments in the last specific aim (4) will test the importance of the endogenous c-Rel subunit of NF-iB for neuronal survival using neurons from c-Re! "knockout" mice. Together these experiments will test the importance of NF-kB for neurotrophinregulated survival and they will uncover important new information concerning the mechanisms by which neurotrophins protect neurons from cell death.